Evidence for variable selective pressures at MC1R

Abstract

It is widely assumed that genes that influence variation in skin and hair pigmentation are under selection. To date, the melanocortin 1 receptor (MC1R) is the only gene identified that explains substantial phenotypic variance in human pigmentation. Here we investigate MC1R polymorphism in several populations, for evidence of selection. We conclude that MC1R is under strong functional constraint in Africa, where any diversion from eumelanin production (black pigmentation) appears to be evolutionarily deleterious. Although many of the MC1R amino acid variants observed in non-African populations do affect MC1R function and contribute to high levels of MC1R diversity in Europeans, we found no evidence, in either the magnitude or the patterns of diversity, for its enhancement by selection; rather, our analyses show that levels of MC1R polymorphism simply reflect neutral expectations under relaxation of strong functional constraint outside Africa.

Figure 1

MC1R variation. a, Divergent codons and amino acids, between a chimpanzee sequence and the human consensus sequence, with the codon position indicated (blackened circles). Nucleotides that are different from those of the human consensus sequence are shown in uppercase letters. b, Variant haplotypes. The variants are labeled by a single defining amino acid change compared with the human consensus sequence. Both the codon position (numbers) and variant codons are indicated (blackened circles). Nucleotide that differ from those of the consensus sequence are shown in uppercase letters.

Figure 2

Gene trees connecting MC1R haplotypes through mutation events. Mutations in codon sequences, relative to the consensus sequence, are shown in uppercase letters. The MC1R consensus sequence is indicated (blackened circles), as is the root haplotype (gray-shaded circles), which is determined by comparison with a chimpanzee sequence. Variant haplotypes are labeled by a single defining amino acid change, compared with the human consensus sequence. Circled areas for haplotypes are proportional to their frequencies, not to sample numbers. a, European and Asian samples. b, African samples.